Alzheimer’s disease (AD) is a neurodegenerative disorder resulting in memory loss and decline of a person’s ability to function independently. It is the most common cause of dementia and a leading cause of death in the U.S. Currently, there is no cure; therefore, further research is important. Scientists believe AD occurs due to the buildup of plaques created by the aggregation of protein fragments, called Amyloid Beta (Aβ), on nerve cells. An Aβ structure of interest is Aβ(1-42), the first 42 amino acids of the Aβ peptide. Stability of Aβ(1-42) comes from hydrogen bonding within the backbone of the peptides. Plaques are formed when many Aβ peptides interact and form intermolecular bonds. The goal of this research is to discover a drug that interrupts interactions between Aβ fibrils. Because stilbenoids contain carbon rings and hydroxyl groups, they are likely to interact with Aβ, destabilize the fibril structure, and thus prevent aggregation. Using computational chemistry methods, interactions between the stilbenoid and Aβ can be modeled to understand the development of AD. Computational methods such as molecular docking and molecular dynamics (MD) simulations were used to evaluate eleven common stilbenoids. MD predicts the dynamics interactions between these potential stilbenoid drug molecules and Aβ in physiological conditions, which helps determine the efficiency of these stilbenoids as aggregation inhibitors of Aβ. Preliminary docking results show the stilbenoid structures dock to the N-terminus of Aβ(1-42), which is consistent with published literature. These results are believed to be due to the rings on the stilbenoids interacting with Aβ’s aromatic amino acids in the N-terminus area. Using results from structural and energetic analyses, the effectiveness of the potential stilbenoid inhibitor molecules in breaking up the Aβ aggregates are determined so that a mechanism can be proposed for Aβ disaggregation.

Computational investigation of stilbenoids as aggregation inhibitors of Amyloid β as it relates to Alzheimer’s Disease

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ACS Fall 2022

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